In various industrial fields, there has been a constant demand for a technique of an effective and rapid preparation of very fine particles in regular size. Such fine particles in regular size have many advantages. Among them, good flowability and little deviation in particle interaction are especially very advantageous in industrial applications. For example, in the drug industry, the particle size of a therapeutic agent greatly affects the dissolution rate, bioavailability, formulation and the like, and as deviation in the interaction between the particles of a therapeutic agent becomes smaller, the overall stability of the therapeutic agent improves.
In medicinal products, if the particle of a therapeutic agent is made into nanoscale size, the following advantages are obtained. First of all, for drugs having a small enteral absorption rate in oral administration, more absorption can be achieved and thus the bioavailability of the therapeutic agent can be increased, as compared with those of a bigger size. Furthermore, the dosage form of drugs can vary. For instance, a drug that has been administered only via oral route may be administered by inhalation. In a controlled-release drug formulation, the release rate of a therapeutic agent is a very important factor. When the particle size of the therapeutic agent is formed in nanoscale, the particle size becomes relatively more uniform, thus the release rate can become more expectable, allowing the provision of more effective therapeutic agent.
In order to capitalize on the advantages of uniform nanoparticles as described above, many attempts have been made to prepare an active ingredient as a nanoparticle. For this object, mechanical techniques such as crushing, grinding, milling and the like have been conventionally employed to make relatively large particles smaller. Recently in the pharmaceutical industry, a method using an air-jet mill for milling a large amount of drugs to a size range suitable for medicinal or pharmaceutical use has been commonly used. However, according to U.S. Pat. No. 5,534,270 and Lachman, et al. [The Theory and Practice of Industrial Pharmacy, Chapter 2, “Milling,” p. 45, (1986)], such conventional mechanical processes have been generally recognized as having a limitation of possible minimum particle size of about tens of micrometers.
It has been reported that nanoscale fenofibrate was obtained by a method comprising mixing fenofibrate and sodium chloride (weight ratio of 1:7) using a ball mill and dry-grinding the mixture using an attritor mill [Vandym N. Mocahlin et al., Pharmaceutical Research, Vol. 26, No. 6, 1365˜1370, June 2009], wherein sodium chloride is a very hard material and when it is ground by a ball mill, it serves as a grind media and at the same time prevents re-coagulation of the ground fenofibrate.
Keiji Yamamoto et al. asserted that nanoparticles of drug may be prepared by grinding the drug along with cyclodextrin using a rod mill [Chem. Pharm. Bull. 55(3), 359-363 (2007)]. They asserted that the amount of cyclodextrin used in this method is about twice the active ingredient in molar ratio—i.e., about four times in weight ratio, and that humidity for hydrating all used cyclodextrin is needed and it is disadvantageous if the humidity is too high or too low.
Furthermore, in WO 2008/126797, Hirokawa, Takashi et al. disclose a process for providing a nanoscale active ingredient by mixing sodium chloride and polyol compound with an active ingredient and then subjecting it to a wet-milling process without the use of grinding media. However, these processes use excessive sodium chloride and polyol compound, and thus essentially require a step for removing sodium chloride and polyol compound in order to use the obtained nanoparticles in medicinal products.
U.S. Pat. No. 5,202,129 discloses a method for preparing fine particles of a poorly water-soluble drug by mixing the drug with 2.5 times or more of low-molecular weight saccharide or sugar alcohol and then dry-grinding the mixture. However, this method has a problem in that because a large amount of saccharide is used, for actual use in medicinal products, it is necessary to remove the saccharide by dispersing the ground mixture in water, filtering the dispersed mixture and drying the filtered mixture.
U.S. Pat. No. 5,145,684 discloses a method for preparing particles of a poorly water-soluble drug in a size of hundreds of nanometers by wet-milling the poorly water-soluble drug in the presence of a non-crosslinked polymer. This technique should be applied after preparing the drug in a particle size of 100 micrometers or less by using a conventional milling process. In this method, the time for preparing particles within the target size range depends on the mechanical device used therefor. When a ball mill is used, 5 days or longer is required. However, when a high shear media mill is used, the particles can be prepared within 1 day. However, since the nanoparticles obtained in this method are in liquid phase, in order to make them in powder type, a process of spray dry or freeze dry should be conducted. During the drying process, however, coagulation of particles occurs and when the obtained powder is re-dispersed in liquid, it is difficult to obtain a dispersion of particles in nanometer scale. In order to solve such a problem, U.S. Pat. No. 5,302,401 discloses an anti-coagulation agent employed during lyophilization. Additionally, U.S. Pat. No. 6,592,903 B2 discloses use of a stabilizer, a surfactant and an anti-coagulation agent during a spray-dry process. Furthermore, US Patent Application Publication No. 2003/0185869 A1 discloses an application of a wet milling technique using lysozyme as a surface stabilizer to some poorly soluble drugs. However, in this case, since the surface stabilizer is a protein, there are many restrictions in drying and accordingly only the preparation in liquid phase is disclosed.
US Patent Application Publication No. 2002/0168402 discloses a method for preparing nanoparticles using piston gap homogenization. However, in order to use piston gap homogenization, a pretreatment process using jet mill or hammer mill for grinding particles into uniform size is required. In addition, because this process is not suitable for highly viscous solutions, it should be performed in a state where the concentration of active gradient is low.
As another conventional method, there is a recrystallization technique which provides fine particles of an active ingredient by changing the environment of a solution containing the active ingredient dissolved therein to cause the precipitation or crystallization of the solute. The recrystallization technique can be carried out in two different ways: one being comprised of dissolving a therapeutic agent in a suitable solvent and lowering the temperature, thereby changing the solubility of the therapeutic agent to precipitate particles; and the other being comprised of adding an antisolvent to a solution containing the therapeutic agent dissolved therein, thereby decreasing the dissolving ability of the solvent to precipitate particles. However, most such recrystallization techniques usually require use of an organic solvent harmful to humans, and flocculation or coagulation of the particles in a wet condition occurs during a drying process after filtration of the precipitated particles. As a result, the final particles may not be uniform in size.
US Patent Application Publication No. 2003/0104068 A1 discloses a method for preparing fine particles by dissolving a polymer in an organic solvent, dissolving or dispersing a protein drug therein, rapidly cooling the solution to ultra-low temperature for solidification, and lyophilizing the product to provide fine powder. In this case, however, the protein drug may be denatured by the contact with an organic solvent, and the process needs the rapid cooling and lyophilizing processes, and thus is not economical.
In addition, there are techniques of reducing particle size by using emulsification. Such emulsifying methods are commonly used in the cosmetic field, and provide fine particles by melting poorly water-soluble substances by heat or dissolving them in an organic solvent, and adding the melted or dissolved substances to an aqueous solution containing a surfactant dissolved therein, with stirring at high speed or with sonication to disperse the added substances. However, in this case, a step for removing water is required to provide fine particles in powder form, and many restrictions are generated during the water-removal step. Furthermore, when an organic solvent is used to dissolve the poorly water-soluble substance, there always is a concern that the residual organic solvent will be harmful to humans.
US Patent Application Publication No. 2004/0067251 A1 discloses a method for preparing fine particles by dissolving an active ingredient in an organic solvent and spraying the resulting solution into an aqueous solution containing a surfactant dissolved therein. This method uses an organic solvent, and since the prepared particles exist in an aqueous phase, a drying process is required for removing water used as solvent, to render the particles in powder form. During the drying process, however, coagulation of the particles occurs and thus it is hard to re-disperse them in nanoscale size.